Increased food intake (FI) or hyperphagia, activation of the hypothalamic-pituitary-adrenal-renal (HPA) axis and decreased gonadal function (GF) are well-described concomitants of uncontrolled diabetes. Recent studies suggest that reduced levels of the adipocyte hormone leptin may contribute to the pathogenesis of this disorder. Leptin acts directly in the central nervous system to reduce FI and body weight by altering discrete neuronal signaling systems. Leptin suppresses neuropeptide Y (NPY), a key hypothalamic peptide that stimulates feeding behavior, activates the HPA axis, and decreases GF. In addition, leptin increases expression of mRNA for corticotrophin releasing hormone (CRH) and proopiomelanocortin (POMC), two hypothalamic neuropeptides that have been shown to reduce FI, cause weight loss and affect the HPA axis and GF. Circulating leptin levels are reduced in uncontrolled insulin- deficient diabetes, suggesting that leptin deficiency contributes to these neuroendocrine responses in the diabetic state. Consistent with this hypothesis, uncontrolled diabetes raises NPY and lowers CRH expression in the hypothalamus; its effects on POMC are unknown. Experiments proposed here will isolate the contribution made by leptin deficiency to the pathogenesis of diabetic hyperphagia, activation of the HPA axis and decrease in GF. This will be accomplished by examining the effects of physiological leptin replacement in diabetic rats on food intake, corticosterone, and gonadal hormones as well as on hypothalamic gene expression. If leptin deficiency contributes to neuroendocrine disturbances that accompany uncontrolled diabetes, these will be reversed by the maintenance of normal leptin levels in diabetic rats and this will coincide with detectable changes in hypothalamic neuropeptide expression. These studies will not only provide insight into the relative role of leptin deficiency in the hypothalamic responses to uncontrolled diabetes, but will robustly test the role of leptin in the regulation of FI, the HPA axis and GF.